TY - JOUR

T1 - Influence of plasma halide, pseudohalide and nitrite ions on myeloperoxidase-mediated protein and extracellular matrix damage

AU - Xu, Shuqi

AU - Chuang, Christine Y.

AU - Malle, Ernst

AU - Gamon, Luke F.

AU - Hawkins, Clare L.

AU - Davies, Michael J.

N1 - Publisher Copyright: © 2022 The Authors

PY - 2022

Y1 - 2022

N2 - Myeloperoxidase (MPO) mediates pathogen destruction by generating the bactericidal oxidant hypochlorous acid (HOCl). Formation of this oxidant is however associated with host tissue damage and disease. MPO also utilizes H2O2 to oxidize other substrates, and we hypothesized that mixtures of other plasma anions, including bromide (Br−), iodide (I−), thiocyanate (SCN−) and nitrite (NO2−), at normal or supplemented concentrations, might modulate MPO-mediated HOCl damage. For the (pseudo)halide anions, only SCN− significantly modulated HOCl formation (IC50 ∼33 μM), which is within the normal physiological range, as judged by damage to human plasma fibronectin or extracellular matrix preparations detected by ELISA and LC-MS. NO2− modulated HOCl-mediated damage, in a dose-dependent manner, at physiologically-attainable anion concentrations. However, this was accompanied by increased tyrosine and tryptophan nitration (detected by ELISA and LC-MS), and the overall extent of damage remained approximately constant. Increasing NO2− concentrations (0.5–20 μM) diminished HOCl-mediated modification of tyrosine and methionine, whereas tryptophan loss was enhanced. At higher NO2− concentrations, enhanced tyrosine and methionine loss was detected. These analytical data were confirmed in studies of cell adhesion and metabolic activity. Together, these data indicate that endogenous plasma levels of SCN− (but not Br− or I−) can modulate protein modification induced by MPO, including the extent of chlorination. In contrast, NO2− alters the type of modification, but does not markedly decrease its extent, with chlorination replaced by nitration. These data also indicate that MPO could be a major source of nitration in vivo, and particularly at inflammatory sites where NO2− levels are often elevated.

AB - Myeloperoxidase (MPO) mediates pathogen destruction by generating the bactericidal oxidant hypochlorous acid (HOCl). Formation of this oxidant is however associated with host tissue damage and disease. MPO also utilizes H2O2 to oxidize other substrates, and we hypothesized that mixtures of other plasma anions, including bromide (Br−), iodide (I−), thiocyanate (SCN−) and nitrite (NO2−), at normal or supplemented concentrations, might modulate MPO-mediated HOCl damage. For the (pseudo)halide anions, only SCN− significantly modulated HOCl formation (IC50 ∼33 μM), which is within the normal physiological range, as judged by damage to human plasma fibronectin or extracellular matrix preparations detected by ELISA and LC-MS. NO2− modulated HOCl-mediated damage, in a dose-dependent manner, at physiologically-attainable anion concentrations. However, this was accompanied by increased tyrosine and tryptophan nitration (detected by ELISA and LC-MS), and the overall extent of damage remained approximately constant. Increasing NO2− concentrations (0.5–20 μM) diminished HOCl-mediated modification of tyrosine and methionine, whereas tryptophan loss was enhanced. At higher NO2− concentrations, enhanced tyrosine and methionine loss was detected. These analytical data were confirmed in studies of cell adhesion and metabolic activity. Together, these data indicate that endogenous plasma levels of SCN− (but not Br− or I−) can modulate protein modification induced by MPO, including the extent of chlorination. In contrast, NO2− alters the type of modification, but does not markedly decrease its extent, with chlorination replaced by nitration. These data also indicate that MPO could be a major source of nitration in vivo, and particularly at inflammatory sites where NO2− levels are often elevated.

KW - Extracellular matrix

KW - Fibronectin

KW - Hypochlorous acid

KW - Myeloperoxidase

KW - Nitration

KW - Nitrite

KW - Smooth muscle cells

KW - Thiocyanate

UR - http://www.scopus.com/inward/record.url?scp=85132516042&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2022.06.222

DO - 10.1016/j.freeradbiomed.2022.06.222

M3 - Journal article

C2 - 35718304

AN - SCOPUS:85132516042

VL - 188

SP - 162

EP - 174

JO - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

ER -